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1.
J Ethnopharmacol ; 247: 112232, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31606534

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: 2,3,5,4'-Tetrahydroxy-stilbene-2-O-ß-D-glucoside (TSG) is the main active component of Polygoni Multiflori Radix, a root of the homonymous plant widely used in traditional Chinese medicine. TSG has protective effects on the liver, reduces cholesterol and possesses anti-oxidant, anti-tumor, and anti-atherosclerotic properties. However, the pharmacological effects and mechanisms of action of Polygonum multiflorum on atherosclerosis (AS) have not been studied yet. PURPOSE: The aim of this research was to study the effects of Polygoni Multiflori Radix Praeparata (PMRP) and its major active chemical constituent TSG on AS in ApoE-deficient (ApoE-/-) mice fed with high fat diets to provide a scientific basis in the use of PMRP and TSG against cardiovascular diseases. METHODS: High fat diet induced AS in ApoE-/- mice were treated with PMRP, TSG (low and high doses), and simvastatin (SIM) for 8 weeks. At the end of the treatment, mouse serum lipid levels, triglycerides (TG), and total cholesterol (TC) were measured by an oxidase method (other indicators were determined by ELISA), while the content in oxidized low density lipoprotein (ox-LDL) and the expression of inflammatory factors such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemotactic protein-1 (MCP-1) in the serum and aortic samples were measured by ELISA. Atherosclerotic plaque morphology was evaluated by oil red O in thoracic aorta. In addition, 16S rDNA-V4 hypervariable region genome sequence of all microbes in the fecal sample from each group was analyzed to evaluate potential structure changes in the gut microbiota after treatment with PMRP and TSG. RESULTS: TSG markedly inhibited AS plaque formation in ApoE-/- mice. Furthermore, PMRP and TSG improved lipid accumulation by reducing TG and ox-LDL levels. TSG inhibited inflammation by the down-regulation of IL-6, TNF-α, VCAM-1 and MCP-1 expression in serum, and PMRP inhibited inflammation by reducing VCAM-1, ICAM-1 and CCRA expression in aortic tissue. In addition, TSG reduced or prevented AS by the regulation of the composition of the overall gut microbiota, such as Firmicutes, Bacteroidetes, Tenericutes, Proteobacteria phyla, Akkermensia genera and Helicobacter pylori. CONCLUSION: PMRP and TSG improved lipid accumulation and inflammation, and regulated the intestinal microbial imbalance in ApoE-/- mice. TSG exerted a preventive effect in the development and progression of AS.


Assuntos
Aterosclerose/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Glucosídeos/farmacologia , Inflamação/tratamento farmacológico , Polygonum/química , Estilbenos/farmacologia , Administração Oral , Animais , Aorta/patologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/patologia , Quimiocina CCL2/imunologia , Quimiocina CCL2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Microbioma Gastrointestinal/imunologia , Glucosídeos/uso terapêutico , Humanos , Inflamação/sangue , Inflamação/etiologia , Molécula 1 de Adesão Intercelular/imunologia , Molécula 1 de Adesão Intercelular/metabolismo , Lipoproteínas LDL/sangue , Masculino , Camundongos , Camundongos Knockout para ApoE , Estilbenos/uso terapêutico , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/imunologia , Molécula 1 de Adesão de Célula Vascular/metabolismo
2.
Cell Mol Biol (Noisy-le-grand) ; 65(7): 55-59, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31880518

RESUMO

To investigate the effect of polydatin on glucose transporter, blood glucose homeostasis and renal injury in streptozotocin (STZ)-induced diabetic rats. The in vitro inhibitory effect of polydatin on sodium-glucose cotransporter-1 (SGLT1) and 2 (SGLT2) was determined using HEK293 cells. The inhibitory effect of polydatin on GLUT1 and GLUT4 was evaluated using 3T3-L1 adipocytes. Streptozotocin-induced diabetic rats were used for this study. Fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), urea nitrogen, serum creatinine and urinary protein were determined using biochemical analyzer. Histopathological examination was performed on renal tissue. Serum levels of interleukin 1ß (IL-1ß), tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and C-reactive protein (CRP) were also determined. Polydatin significantly inhibited SGLT1/2 and exhibited high selectivity for both GLUT1 and GLUT4. It significantly and dose-dependently decreased hyperglycemia, enhanced urine glucose excretion in the diabetic rats. The polydatin treatment significantly ameliorated symptoms of DN such as polyuria, polydipsia and hyperphagia. The hypoglycemic effect of polydatin was maintained throughout the treatment period. In addition,the levels of IL-1ß, TNF-α, MCP-1 and CRP were significantly reduced in treated group. Treatment with polydatin significantly ameliorated most of the structural and morphological changes induced by STZ. Moreover, the levels of urinary protein, serum creatinine and urea nitrogen were significantly reduced after treatment with polydatin.  As a potential dual inhibitor of SGLT1/2, polydatin has high selectivity for GLUT1 and GLUT4. Its long-term administration delays the development of DN, protects renal function and ameliorates renal tissue injury.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/uso terapêutico , Hiperglicemia/tratamento farmacológico , Estilbenos/uso terapêutico , Células 3T3-L1 , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Células HEK293 , Humanos , Hiperglicemia/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo
3.
Oxid Med Cell Longev ; 2019: 1243215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871537

RESUMO

Excessive fructose consumption induces oxidative stress and myocardial fibrosis. Antioxidant compound pterostilbene has cardioprotective effect in experimental animals. This study is aimed at investigating how fructose drove fibrotic responses via oxidative stress in cardiomyocytes and explored the attenuation mechanisms of pterostilbene. We observed fructose-induced myocardial hypertrophy and fibrosis with ROS overproduction in rats. Paired-like homeodomain 2 (Pitx2c) increase, microRNA-15b (miR-15b) low expression, and p53 phosphorylation (p-p53) upregulation, as well as activation of transforming growth factor-ß1 (TGF-ß1)/drosophila mothers against DPP homolog (Smads) signaling and connective tissue growth factor (CTGF) induction, were also detected in fructose-fed rat hearts and fructose-exposed rat myocardial cell line H9c2 cells. The results from p53 siRNA or TGF-ß1 siRNA transfection showed that TGF-ß1-induced upregulation of CTGF expression and p-p53 activated TGF-ß1/Smads signaling in fructose-exposed H9c2 cells. Of note, Pitx2c negatively modulated miR-15b expression via binding to the upstream of the miR-15b genetic loci by chromatin immunoprecipitation and transfection analysis with pEX1-Pitx2c plasmid and Pitx2c siRNA, respectively. In H9c2 cells pretreated with ROS scavenger N-acetylcysteine, or transfected with miR-15b mimic and inhibitor, fructose-induced cardiac ROS overload could drive Pitx2c-mediated miR-15b low expression, then cause p-p53-activated TGF-ß1/Smads signaling and CTGF induction in myocardial fibrosis. We also found that pterostilbene significantly improved myocardial hypertrophy and fibrosis in fructose-fed rats and fructose-exposed H9c2 cells. Pterostilbene reduced cardiac ROS to block Pitx2c-mediated miR-15b low expression and p-p53-dependent TGF-ß1/Smads signaling activation and CTGF induction in high fructose-induced myocardial fibrosis. These results firstly demonstrated that the ROS-driven Pitx2c/miR-15b pathway was required for p-p53-dependent TGF-ß1/Smads signaling activation in fructose-induced myocardial fibrosis. Pterostilbene protected against high fructose-induced myocardial fibrosis through the inhibition of Pitx2c/miR-15b pathway to suppress p-p53-activated TGF-ß1/Smads signaling, warranting the consideration of Pitx2c/miR-15b pathway as a therapeutic target in myocardial fibrosis.


Assuntos
Fibrose/tratamento farmacológico , Fibrose/metabolismo , Frutose/toxicidade , Cardiopatias/tratamento farmacológico , Cardiopatias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estilbenos/uso terapêutico , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
4.
Eur J Pharmacol ; 859: 172526, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31283935

RESUMO

Pterostilbene (PTE) is a natural dimethylated analog of resveratrol, which exerts antioxidative, hypolipidemic and hypoglycemic effects; however, the underlying mechanism is not yet clear. In this study, we evaluated the effects of PTE on diabetic rats and clarified the underlying mechanism. Diabetes was induced in rats by streptozotocin (STZ) and a high-sugar and high-fat diet. Rats were then treated with PTE (20, 40 and 80 mg/kg/d) for 8 weeks. Oral glucose tolerance test (OGTT) was performed to measure the glycometabolism of the diabetic rats at the end of the treatment. Fasting blood glucose (FBG), fasting insulin (FINS) and lipid profile were determined using an automatic biochemistry analyzer and serum inflammatory factors were analyzed by enzyme-linked immunosorbent assay. Serum superoxide dismutase (SOD) and malondialdehyde (MDA) were also analyzed by spectrophotometry to evaluate the anti-oxidant effects. The expression of proteins of PPARγ and PI3K/Akt signaling pathway related proteins in adipose tissue of the diabetic rats was analyzed by Western blotting. PTE treatment significantly reduced weight loss, FBG, insulin resistance, serum lipid levels and inflammatory factors. PTE treatment also inhibited oxidative stress by decreasing MDA expression and increasing SOD expression. Simultaneously, PTE treatment significantly ameliorated morphological impairment of the pancreas in diabetic rats. Furthermore, PTE treatment significantly increased the protein expression of PPARγ, PI3K, p-Akt, GLUT4 and IRS-1 in adipose tissues of diabetic rats. This study suggests that PTE can exert antidiabetic effects via the PI3K/Akt signaling pathway.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Jejum/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Lipídeos/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos , Ratos Sprague-Dawley , Estilbenos/uso terapêutico
5.
Chem Pharm Bull (Tokyo) ; 67(7): 648-653, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257320

RESUMO

Diabetic embryopathy is a diabetic complication, in which maternal hyperglycemia in early pregnancy causes birth defects in newborn infants. Under maternal diabetic conditions, hyperglycemia disturbs intracellular molecular activities and organelles functions. These include protein misfolding in the endoplasmic reticulum (ER), overproduction of reactive oxygen species (ROS) in mitochondria, and high levels of nitric oxide (NO). The resultant ER, oxidative, and nitrosative stresses activate apoptotic machinery to cause cell death in the embryo, ultimately resulting in developmental malformations. Based on the basic research data, efforts have been made to develop interventional strategies to alleviate the stress conditions and to reduce embryonic malformations. One of the challenges in birth defect prevention is to identify effective and safe agents to be used in pregnancy. One approach is to search and characterize naturally occurring phytochemicals, including flavonoids, curcuminoids and stilbenoids, for use in prevention of diabetic embryopathy.


Assuntos
Anormalidades Congênitas/prevenção & controle , Compostos Fitoquímicos/uso terapêutico , Gravidez em Diabéticas/prevenção & controle , Curcumina/química , Curcumina/farmacologia , Curcumina/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Estresse Oxidativo/efeitos dos fármacos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Gravidez , Estilbenos/química , Estilbenos/farmacologia , Estilbenos/uso terapêutico
6.
Chem Biol Interact ; 310: 108754, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31323227

RESUMO

Diabetic cardiomyopathy (DCM) is one of the leading causes of morbidity and mortality in diabetic patients. Piceatannol (PIC) has protective effects against cardiovascular disease; however, it remains unknown whether it also protects against DCM. A Cell Counting Kit-8 (CCK-8) assay was used to evaluate the effects of PIC on the viability of high glucose (HG)-induced H9C2 cells. Protein expression and mRNA levels were detected by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. In vivo, physical and biochemical analyses, together with transthoracic echocardiography and hemodynamic measurements, were used to detect the effects of PIC treatment on cardiac function in DCM rats. Reactive oxygen species production was determined using an ELISA kit, and inflammatory cytokines were detected by RT-PCR. Pathological changes were assessed by hematoxylin-eosin staining, immunohistochemical staining, and TUNEL staining. According to the results, PIC treatment improved cell viability and inhibited cell apoptosis in HG-induced H9C2 cardiac myoblasts. In addition, PIC not only attenuated the over-production of interleukin-6 (IL-6) (P < 0.05) and tumor necrosis factor alpha (TNF-α) (P < 0.05), but also improved the expression of nuclear factor E2-related factor 2 (Nrf2) (P < 0.05) and heme oxygenase-1 (HO-1) (P < 0.01). Importantly, knockdown of Nrf2 suppressed PIC-mediated activation of the Nrf2/HO-1 pathway and abolished its anti-inflammatory effects. In vivo, oral administration of PIC suppressed STZ-induced inflammation, oxidative stress hypertrophy, fibrosis(myocardial collagen volume fraction in 5 mg/kg and 10 mg/kg PIC group was decreased 25.83% and 55.61% compared with the DM group), and apoptosis(Caspase-3 level in 5 mg/kg and 10 mg/kg PIC group was decreased 13.21% and 33.91% compared with the DM group), thereby relieving cardiac dysfunction and improving both fibrosis and pathological changes in cardiac tissues of diabetic rats. These findings define for the first time that the effects of PIC against DCM can be attributed to its role in inflammation and oxidative stress inhibition.


Assuntos
Cardiomiopatias Diabéticas/tratamento farmacológico , Inflamação/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais , Estilbenos/farmacologia , Animais , Linhagem Celular , Heme Oxigenase-1/metabolismo , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ratos , Estilbenos/uso terapêutico
7.
Int J Mol Sci ; 20(11)2019 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-31159515

RESUMO

: Cellular senescence is a state of cell cycle arrest characterized by a distinct morphology, gene expression pattern, and secretory phenotype. It can be triggered by multiple mechanisms, including those involved in telomere shortening, the accumulation of DNA damage, epigenetic pathways, and the senescence-associated secretory phenotype (SASP), and so on. In current cancer therapy, cellular senescence has emerged as a potent tumor suppression mechanism that restrains proliferation in cells at risk for malignant transformation. Therefore, compounds that stimulate the growth inhibition effects of senescence while limiting its detrimental effects are believed to have great clinical potential. In this review article, we first review the current knowledge of the pro- and antitumorigeneic functions of senescence and summarize the key roles of telomerase in the regulation of senescence in tumors. Second, we review the current literature regarding the anticancer effects of stilbene compounds that are mediated by the targeting of telomerase and cell senescence. Finally, we provide future perspectives on the clinical utilization of stilbene compounds, especially resveratrol and pterostilbene, as novel cancer therapeutic remedies. We conclude and propose that stilbene compounds may induce senescence and may potentially be used as the therapeutic or adjuvant agents for cancers with high telomerase activity.


Assuntos
Antineoplásicos/uso terapêutico , Senescência Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Estilbenos/uso terapêutico , Telomerase/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Estilbenos/farmacologia , Telomerase/metabolismo
8.
Mini Rev Med Chem ; 19(19): 1599-1610, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31161987

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors which belong to the ligand-activated nuclear receptor superfamily. They are ubiquitously expressed throughout the body. So far, three major subtypes have been identified, PPARα, PPARß/δ and PPARγ. They are crucial for lipid and glucose metabolism and are also involved in the regulation of several types of tumors, inflammation, cardiovascular diseases and infertility. The importance of these transcription factors in physiology and pathophysiology has been largely investigated. Synthetic PPAR ligands are widely used in the treatment of dyslipidemia (e.g. fibrates - PPARα activators) or in diabetes mellitus (e.g. thiazolidinediones - PPARγ agonists) while a new generation of dual agonists reveals hypolipemic, hypotensive, antiatherogenic, anti-inflammatory and anticoagulant action. Many natural ligands, including polyphenolic compounds, influence the expression of these receptors. They have several health-promoting properties, including antioxidant, anti-inflammatory, and antineoplastic activities. Resveratrol, a stilbene polyphenol, is a biological active modulator of several signaling proteins, including PPARs. Given the enormous pharmacological potential of resveratrol, stilbene-based medicinal chemistry had a rapid increase covering various areas of research. The present review discusses ligands of PPARs that contain stilbene scaffold and summarises the different types of compounds on the basis of chemical structure.


Assuntos
PPAR alfa/metabolismo , PPAR gama/metabolismo , Estilbenos/química , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Dislipidemias/tratamento farmacológico , Dislipidemias/patologia , Humanos , Ligantes , PPAR alfa/agonistas , PPAR gama/agonistas , Estilbenos/metabolismo , Estilbenos/uso terapêutico , Tiazolidinedionas/química
9.
Free Radic Res ; 53(7): 815-827, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31223033

RESUMO

Insulin resistance (IR) is known to precede onset of type 2 diabetes and increased oxidative stress appears to be a deleterious factor leading to IR. In this study, we evaluated ability of pterostilbene (PTS), a methoxylated analogue of resveratrol and a known antioxidant, to reverse palmitic acid (PA)-mediated IR in HepG2 cells. PTS prevented reactive oxygen species (ROS) formation and subsequent oxidative lipid damage by reducing the expression of NADPH oxidase 3 (NOX3) in PA treated HepG2 cells. Hepatic glucose production was used as a measure of IR and PTS reversed PA-mediated increase in hepatic glucose production by reducing expression of genes coding for gluconeogenic enzymes namely glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase (PEPCK), and pyruvate carboxylase (PC); and their transcription factors cAMP response element binding protein (CREB) and fork head class Box O (FOXO1) along with its coactivator peroxisome proliferator-activated receptor gamma co-activator-1 α (PGC1α). PTS reversed PA-mediated activation of c-Jun N-terminal kinase (JNK), which in turn altered insulin signalling pathway by phosphorylating IRS-1 at Ser 307, leading to inhibition of phosphorylation of Akt and GSK-3ß. PTS also reduced PA-mediated lipid accumulation by reducing expression of transcription factors SREBP1c and PPARα. SREBP1c activates genes involved in fatty acid and triglyceride synthesis while PPARα activates CPT1, a rate limiting enzyme for controlling entry and oxidation of fatty acids into mitochondria. PTS, however, did not influence PA uptake confirmed by using BODIPY-labelled fluorescent C16 fatty acid analogue. Thus, our data provides a possible mechanistic explanation for reversal of PA-mediated IR in HepG2 cells.


Assuntos
Resistência à Insulina/genética , Ácido Palmítico/efeitos adversos , Estilbenos/uso terapêutico , Triglicerídeos/metabolismo , Células Hep G2 , Humanos , Estresse Oxidativo , Estilbenos/farmacologia
10.
Nutrients ; 11(5)2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31035507

RESUMO

Excessive fat accumulation within the liver is known as "simple hepatic steatosis", which is the most benign form of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to determine whether pterostilbene improves this hepatic alteration in Zucker (fa/fa) rats. Animals were distributed in two experimental groups (n = 10) and fed a standard laboratory diet. Rats in the pterostilbene group were given a dose of 30 mg/kg body weight/d for six weeks. After sacrifice, serum glucose, transaminase, and insulin concentrations were quantified and the liver triacylglycerol content and fatty acid profile was analyzed. Different pathways of triacylglycerol metabolism in liver were studied, including fatty acid synthesis and oxidation, triglyceride assembly, fatty acid uptake, and glucose uptake. With pterostilbene administration, a reduction in insulin concentrations (consequently in the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)) and hepatic triacylglycerol content were observed. No effects were observed in pterostilbene-treated rats in the activity of de novo lipogenesis enzymes. An improvement in the fatty acid profile was observed in pterostilbene-treated rats. In conclusion, pterostilbene is a useful molecule to reduce liver steatosis. Its delipidating effect is due, at least in part, to reduced fatty acid availability and triacylglycerol synthesis, as well as to an increased very low-density lipoprotein assembly and fatty acid oxidation.


Assuntos
Fígado Gorduroso/prevenção & controle , Fígado/metabolismo , Obesidade/metabolismo , Estilbenos/uso terapêutico , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/enzimologia , RNA/genética , RNA/metabolismo , Distribuição Aleatória , Ratos , Ratos Zucker , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estilbenos/administração & dosagem
11.
Paediatr Drugs ; 21(2): 95-106, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30941653

RESUMO

Increasing knowledge in the field of rare diseases has led to new therapeutic approaches in the last decade. Treatment strategies have been developed after elucidation of the underlying genetic alterations and pathophysiology of certain diseases (e.g., in osteogenesis imperfecta, achondroplasia, hypophosphatemic rickets, hypophosphatasia and fibrodysplasia ossificans progressiva). Most of the drugs developed are specifically designed agents interacting with the disease-specific cascade of enzymes and proteins involved. While some are approved (asfotase alfa, burosumab), others are currently being investigated in phase III trials (denosumab, vosoritide, palovarotene). To offer a multi-disciplinary therapeutic approach, it is recommended that patients with rare skeletal disorders are treated and monitored in highly specialized centers. This guarantees the greatest safety for the individual patient and offers the possibility of collecting data to further improve treatment strategies for these rare conditions. Additionally, new therapeutic options could be achieved through increased awareness, not only in the field of pediatrics but also in prenatal and obstetric specialties. Presenting new therapeutic options might influence families in their decision of whether or not to terminate a pregnancy with a child with a skeletal disease.


Assuntos
Doenças Musculoesqueléticas/tratamento farmacológico , Doenças Raras/tratamento farmacológico , Fosfatase Alcalina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Criança , Denosumab/uso terapêutico , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Mutação , Gravidez , Pirazóis/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Estilbenos/uso terapêutico
12.
J BUON ; 24(1): 296-300, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941984

RESUMO

PURPOSE: Kidney cancer is a lethal type of malignancy with high mortality. The chemotherapeutic agents used for the treatment of kidney cancer have several adverse effects, therefore, there is need to explore new molecules for the treatment of this disease. In the current study, the anticancer activity of plant-derived stilbenoid Mulberroside-A (MA) was evaluated against the A498 kidney cancer cell line and the underlying mechanism was explored. METHODS: The A498 cell viability was determined by WST-1 assay. DAPI and AO/EB staining were employed for the detection of apoptosis. Matrigel and wound heal assay were used for cell invasion and migration study, respectively. Protein expression was checked by immunoblotting. RESULTS: The results showed that MA could inhibit the growth of the A498 cells dose-dependently. The IC50 of 20 µM was observed for MA against the kidney cancer A498 cells. The anticancer effects of MA against these cells were due to apoptotic cell death. Apoptosis was associated with alteration of the Bax/bcl-2 ratio. In addition, MA could also suppress the migration and invasion of the kidney cancer A498 cells by targeting EGFR signalling pathway. CONCLUSION: In conclusion, MA may prove beneficial in the treatment of kidney cancer.


Assuntos
Apoptose/efeitos dos fármacos , Dissacarídeos/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Estilbenos/uso terapêutico , Linhagem Celular Tumoral , Movimento Celular , Receptores ErbB/genética , Humanos , Neoplasias Renais/patologia , Invasividade Neoplásica , Transdução de Sinais
13.
Int J Mol Sci ; 20(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939745

RESUMO

The compound, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucoside (TSG), a primary bioactive polyphenolic component of Polygonum multiflorum exerts numerous pharmacological activities. However, its protective effect against non-alcoholic steatohepatitis (NASH), in the context of metabolic syndrome, remains poorly understood. The aim of the present study is to evaluate the effects of TSG treatment on middle-aged (12-mo-old) male LDLr-/- mice, which were fed a high fat diet for 12 weeks to induce metabolic syndrome and NASH. At the end of the experiment, the blood samples of mice were collected for determination of metabolic parameters. Liver and aorta tissues were collected for analysis, such as histology, immunofluorescence, hepatic lipid content, real-time PCR, and western blot. Our data show that TSG treatment improved the different aspects of NASH (steatosis, inflammation, and fibrosis) and atherosclerosis, as well as some of the metabolic basal characteristics. These modulatory effects of TSG are mediated, at least in part, through regulating key regulators of lipid metabolism (SREBP1c, PPARα and their target genes, ABCG5 and CYP7A1), inflammation (CD68, TNF-α, IL-6 and ICAM), fibrosis (α-SMA and TNFß) and oxidative stress (NADPH-oxidase 2/4, CYP2E1 and antioxidant enzymes). These results suggest that TSG may be a promising candidate for preventing and treating the progression of NASH.


Assuntos
Envelhecimento/patologia , Aterosclerose/tratamento farmacológico , Glucosídeos/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estilbenos/uso terapêutico , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aterosclerose/etiologia , Dieta Hiperlipídica/efeitos adversos , Glucosídeos/farmacologia , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Receptores de LDL/genética , Estilbenos/farmacologia
14.
J Pharmacol Exp Ther ; 369(1): 67-77, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30745416

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a very common chronic hepatic disease, with nonalcoholic steatohepatitis (NASH) as a major and severe subcategory that can lead to cirrhosis and hepatocellular carcinoma, and thereby to a high mortality rate. Currently, there has been no approved drug to treat NAFLD or NASH. The current study has presented RLA8, a novel and balanced quadruple agonist for hepatic lipid metabolism and inflammation-related peroxisome proliferator-activated receptors (PPARs)-α/γ/δ and G protein-coupled receptor 40 (GPR40), as a NASH drug candidate. The efficacy of RLA8 to treat NASH was evaluated in vivo using two mouse models induced by methionine/choline-deficient diet or by high-fat diet, respectively. RLA8 was shown to improve serum alanine aminotransferase and high-density lipoprotein cholesterol levels, reduce hepatic free fatty acid and triglyceride levels, and alleviate insulin resistance. Cytokine and lipoperoxide analysis revealed that RLA8 could reduce oxidative stress and inflammation. Histochemical and morphologic examination of mouse livers showed that RLA8 could improve pathologic changes such as steatosis, ballooning, collagen fiber, and inflammation. Polymerase chain reaction and Western blot analyses proved that RLA8 could result in PPARs and GPR40 activation, accompanied by upregulation of the 5'AMP-activated protein kinase-acetyl-CoA carboxylase pathway and inhibition of the expression of lipogenic genes and proteins, which provided more insights into its action mechanisms. In summary, RLA8 has significantly better efficacy to improve NASH-induced liver damage such as steatosis, inflammation, and fibrosis, and, consequently, it represents a new and highly promising NASH drug candidate that is worthy of further investigation and development.


Assuntos
Cirrose Hepática/complicações , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Estilbenos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Estilbenos/uso terapêutico
15.
Vopr Pitan ; 88(1): 17-25, 2019.
Artigo em Russo | MEDLINE | ID: mdl-30811130

RESUMO

Nowadays, more than 300 representatives of stilbenoids are known - a group of natural, synthetic and semi-synthetic biologic active substances, according to the chemical structure belonging to the group of polyphenolic compounds - phenylpropanoids. Representatives of this group of compounds can be detected in such classes of plants as gymnosperms, angiosperms, bryophytes and pteridophyte. The main food sources are the fruits of grapes, blueberries, blueberries, peanuts, cocoa. The history of their detection is associated with the discovery of the protective functions of plants in response to the action of external stimuli. Further study revealed pronounced antioxidant properties. The mechanism of development of many diseases is associated with the processes of oxidation of free radicals, which can be interrupted by the effect of antioxidants. Possible mechanisms of antioxidant action of stilbenoids and their effect on diseases caused by excessive amounts of free radicals have been studied. Stilbenoids increase the tone and stability of the body to stress factors of the environment, improve the adaptive capacity of the nervous and immune systems, show antitumor, cardio-protective and lipid-lowering activities, inhibit lipid peroxidation. In this regard specialized products, food supplements and drugs containing stilbenoids have been developed. However, representatives of this group of compounds have low consumer properties, are sensitive to environmental factors and have low solubility and absorption. Therefore, solutions of these problems are important when developing new foods and drugs. Nowadays, auxiliary substances (solubilizers) are used, as well as such technological methods as microencapsulation, coacervation, polymerization, and others that can cope with problems of instability, poor solubility, low bioavailability, and unsatisfactory consumer qualities, which improve the effect of stilbenoids on the organism.


Assuntos
Antioxidantes , Polifenóis , Estilbenos , Antioxidantes/química , Antioxidantes/classificação , Antioxidantes/uso terapêutico , Arachis/química , Cacau/química , Análise de Alimentos , Frutas/química , Polifenóis/química , Polifenóis/classificação , Polifenóis/uso terapêutico , Estilbenos/química , Estilbenos/classificação , Estilbenos/uso terapêutico
16.
Int Immunopharmacol ; 70: 28-36, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30785088

RESUMO

Polydatin is a glucoside of resveratrol with lots of functional properties in the central nervous system, such as anti-edema, anti-oxidation and anti-inflammation. The purpose of this study was to evaluate the effects of polydatin on traumatic spinal cord injury (SCI) and explore the relative mechanisms. SCI models were established using the weight-drop method in rats, additionally, single polydatin administration (20, 40 mg/kg body weight) remarkably improved motor function of SCI rat, along with decreased nitric oxide (NO) generation and inflammatory factor (IL-1ß, IL-6 and TNF-α) production in spinal cord tissues. Similar to the results of in vivo experiments, the inflammatory response was aggravated with the intervention of lipopolysaccharide (LPS) in BV2 microglia. However, polydatin treatment (1, 2 and 4 µM) inhibited iNOS expression, decreased NLRP3 inflammasome activation, which subsequently relieved microglial inflammation. Above all, our data indicated that polydatin possessed neuroprotective effects in SCI rats, possibly by suppressing iNOS expression and NLRP3 inflammasome activation in microglia.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Glucosídeos/uso terapêutico , Inflamassomos/metabolismo , Microglia/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico , Estilbenos/uso terapêutico , Ferimentos e Lesões/tratamento farmacológico , Animais , Comportamento Animal , Linhagem Celular , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuroproteção , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley
17.
PLoS One ; 14(2): e0212663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785960

RESUMO

As Alzheimer's disease (AD) induces several cellular and molecular damages, it could be interesting to use multi-target molecules for therapeutics. We previously published that trans ε-viniferin induced the disaggregation of Aß42 peptide and inhibited the inflammatory response in primary cellular model of AD. Here, effects of this stilbenoid were evaluated in transgenic APPswePS1dE9 mice. We report that trans ε-viniferin could go through the blood brain barrier, reduces size and density of amyloid deposits and decreases reactivity of astrocytes and microglia, after a weekly intraperitoneal injection at 10 mg/kg from 3 to 6 months of age.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Benzofuranos/uso terapêutico , Inflamação/tratamento farmacológico , Placa Amiloide/tratamento farmacológico , Estilbenos/uso terapêutico , Doença de Alzheimer/patologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Benzofuranos/farmacocinética , Modelos Animais de Doenças , Feminino , Inflamação/patologia , Masculino , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Placa Amiloide/patologia , Estilbenos/farmacocinética
18.
Psychopharmacology (Berl) ; 236(4): 1323-1333, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30607481

RESUMO

BACKGROUND: Hippocampal neurogenesis has been widely considered as one of the potential biological mechanisms for the treatment of depression caused by chronic stress. Many natural products have been reported to be beneficial for neurogenesis. OBJECTIVES: The present study is designed to investigate the effect of dragon's blood extract (DBE) and its biologically active compound, pterostilbene (PTE), on hippocampal neurogenesis. METHODS: The male Sprague-Dawley (SD) rats were used in this study, which were maintained on the normal, DBE and PTE diet groups for 4 weeks before dissection in the normal rat model and behavioral testing in the CUS depression rat model. Meanwhile, DMI-treated rats are subcutaneously injected with DMI (10 mg/kg, i.p.). RESULTS: Results revealed that DBE and PTE have the ability to promote hippocampal neurogenesis. DBE and PTE also promoted the proliferation of neural stem cells isolated from the brain of suckling rats. Oral administration of DBE and PTE induced the proliferation, migration, and differentiation of neural progenitor cells (NPCs) in chronic unexpected stressed (CUS) model rats, and improved the behavioral ability and alleviated depress-like symptoms of CUS rats. It was also observed that PTE treatment significantly induced the expression of neurogenesis-related factors, including BDNF, pERK, and pCREB. CONCLUSION: Oral administration of PTE could affect neurogenesis and it is likely to be achieved via BDNF/ERK/CREB-associated signaling pathways.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Pterocarpus , Estilbenos/uso terapêutico , Animais , Antidepressivos/farmacologia , Células Cultivadas , Depressão/metabolismo , Depressão/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Estilbenos/farmacologia
19.
J Am Acad Dermatol ; 80(3): 714-721, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30612986

RESUMO

BACKGROUND: There is a significant need for novel, safe, and efficacious topical treatments for psoriasis. OBJECTIVE: We assessed the safety and efficacy of tapinarof in a new cream formulation at 2 concentrations and with 2 application frequencies in adults with psoriasis. METHODS: Double-blind, vehicle-controlled, randomized, 6-arm trial (1:1:1:1:1:1) in adults, with psoriasis with body surface involvement ≥1% and ≤15% and Physician Global Assessment (PGA) score ≥2 at baseline. Primary endpoint included PGA of 0 or 1 at week 12 and a 2-grade improvement from baseline. Additional analyses included assessment of ≥75% improvement of Psoriasis Area and Severity Index and mean percent change in Psoriasis Area and Severity Index and body surface area involvement. RESULTS: Treatment success defined by PGA 0 or 1 and a 2-grade improvement at week 12 was statistically significantly higher (at a .05 significance level) in the tapinarof groups (65% [1% twice daily], 56% [1% once daily], 46% [0.5% twice daily], and 36% [0.5% once daily]) than in the vehicle groups (11% [twice daily] and 5% [once daily]) and was maintained for 4 weeks posttreatment. Treatment-emergent adverse events were more frequent in patients treated with tapinarof (85/152, 56%) than vehicle (19/75, 25%) and mild-to-moderate in intensity. Severe treatment-emergent adverse events were reported in all tapinarof groups except the 0.5% once daily group. LIMITATIONS: Large confirmation trials are needed. CONCLUSIONS: Tapinarof cream is efficacious and well tolerated in adult patients with psoriasis.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Resorcinóis/uso terapêutico , Creme para a Pele/administração & dosagem , Estilbenos/uso terapêutico , Adolescente , Adulto , Idoso , Superfície Corporal , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Resorcinóis/administração & dosagem , Índice de Gravidade de Doença , Creme para a Pele/efeitos adversos , Estilbenos/administração & dosagem , Adulto Jovem
20.
Biomater Sci ; 7(3): 860-866, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30698593

RESUMO

Cancer combination therapy based on drug co-delivery systems provides an effective strategy for enhancing treatment efficacy and reducing side effects. In this work, a new strategy through co-delivery of combretastatin A4 disodium phosphate (CA4P) and cisplatin (CDDP) was developed for the local treatment of colon cancer, through an in situ thermo-gelling hydrogel (mPEG-b-PELG). The results indicated that this material possessed concentration-dependent thermogelling properties and tunable in vivo biodegradability. Also, the drug loaded gel could regulate the in vitro drug release behaviors of both CDDP and CA4P, which promoted the in vivo vessel disrupting effects of CA4P compared with a free drug after local treatment for 48 h. Although the drug co-loaded gel induced less in vitro cell death compared with the free drug co-treated group, this drug co-loaded gel depot showed the highest antitumor efficacy compared with the other experimental groups after peritumoral injection toward C26 tumor bearing mice.


Assuntos
Cisplatino/química , Hidrogéis/química , Peptídeos/química , Estilbenos/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/metabolismo , Cisplatino/uso terapêutico , Cisplatino/toxicidade , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Liberação Controlada de Fármacos , Feminino , Humanos , Hidrogéis/síntese química , Camundongos Endogâmicos BALB C , Polímeros/síntese química , Polímeros/química , Estilbenos/metabolismo , Estilbenos/uso terapêutico , Estilbenos/toxicidade , Transplante Heterólogo , Microambiente Tumoral/efeitos dos fármacos
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